Methods of treating neuropeptide Y-related conditions

ABSTRACT

This invention comprises methods of treating treatment or prevention of diseases associated with an excess of neuropeptide Y comprising administration of a compound of the formulae I or II:  
                 
 
     wherein Z is a moiety selected from the group of:  
                 
 
     wherein: R 1  is selected from H, OH or the C 1 -C 12  esters or C 1 -C 12  alkyl ethers thereof, benzyloxy, or halogen; or C 1 -C 4  halogenated ethers including trifluoromethyl ether and trichloromethyl ether; R 2 , R 3 , R 4 , R 5 , and R 6  are H, OH or C 1 -C 12  esters or C 1 -C 12  alkyl ethers thereof, halogens, or C 1 -C 4  halogenated ethers, cyano, C 1 -C 6  alkyl, or trifluoromethyl, with the proviso that, when R 1  is H, R 2  is not OH; Y is the moiety:  
                 
 
     R 7  and R 8  are alkyl or concatenated together to form an optionally substituted, nitrogen-containing ring; or a pharmaceutically acceptable salt thereof.

[0001] This application claims the benefit of U.S. ProvisionalApplication No. 60/216,190, filed Jul. 6, 2000.

[0002] This invention relates to methods of using substituted indolecompounds in the treatment, prevention, inhibition or alleviation ofconditions associated with an excess of neuropeptide Y.

BACKGROUND OF THE INVENTION

[0003] EP 0 802 183 A1 and U.S. Pat. No. 5,780,497 describe substitutedindole compounds of the formulae below:

[0004] as well as their use as estrogenic agents, including thetreatment of bone loss, cardiovascular disease, maladies associated withor resulting from the proliferation or abnormal development ofendometrial or endometrial-like tissues, and disease states or syndromesassociated with estrogen deficiency.

[0005] EP 0 802 184 A1, published Oct. 22, 1997, describes comparableuses for substituted indole compounds of the formulae below.

[0006] Analogous indole compounds having the general structures:

[0007] are described in U.S. Pat. No. 5,880,137 (Miller et al.).

[0008] U.S. Pat. No. 5,776,931 (Nunes et al.) describes the use ofnapthimidazolyl compounds in the treatment of conditions associated withan excess of neuropeptide Y. Similar methods of treatment utilizingraloxifene and its analogs are disclosed in U.S. Pat. No. 5,663,192(Bruns, Jr. et al.). This use of raloxifene and its analogs is alsodescribed by Bruns, Jr. et al. for the treatment of obesity (U.S. Pat.No. 5,567,714), anxiety (U.S. Pat. No. 5,576,337), pain (U.S. Pat. No.5,504,094), and depression (U.S. Pat. No. 5,567,715), each associatedwith an excess of neuropeptide Y. U.S. Pat. No. 5,972,888 (Bue-Valleskeyet al.) teaches the use of a naturally occurring obesity protein incombination with a neuropeptide Y antagonist to treat these samemaladies.

DESCRIPTION OF THE INVENTION

[0009] This invention comprises methods of therapeutic or prophylactictreatment of conditions associated with an excess of neuropeptide Y in amammal, preferably in a human, the methods comprising administering to amammal in need thereof a pharmaceutically effective amount of a compoundof the formulae I or II, below:

[0010] wherein Z is a moiety selected from the group of:

[0011] wherein:

[0012] R₁ is selected from H, OH or the C₁-C₁₂ esters (straight chain orbranched) or C₁-C₁₂ (straight chain or branched or cyclic) alkyl ethersthereof, benzyloxy, or halogens; or C₁-C₄ halogenated ethers includingtrifluoromethyl ether and trichloromethyl ether.

[0013] R₂, R₃, R₅, and R₆ are independently selected from H, OH or theC₁-C₁₂ esters (straight chain or branched) or C₁-C₁₂ alkyl ethers(straight chain or branched or cyclic) thereof, halogens, or C₁-C₄halogenated ethers including trifluoromethyl ether and trichloromethylether, cyano, C₁-C₆ alkyl (straight chain or branched), ortrifluoromethyl, with the proviso that, when R₁ is H, R₂ is not OH;

[0014] R₄ is selected from H, OH or the C₁-C₁₂ esters (straight chain orbranched) or C₁-C₁₂ alkyl ethers (straight chain or branched or cyclic)thereof, benzyloxy, halogens, or C₁-C₄ halogenated ethers includingtrifluoromethyl ether and trichloromethyl ether, cyano, C₁-C₆ alkyl(straight chain or branched), or trifluoromethyl;

[0015] X is selected from H, C₁-C₆ alkyl, cyano, nitro, trifluoromethyl,halogen;

[0016] n is 1, 2 or 3;

[0017] Y is selected from:

[0018] a) the moiety:

[0019] wherein R₇ and R₈ are independently selected from the group of H,C₁-C₆ alkyl, or phenyl optionally substituted by CN, C₁-C₆ alkyl(straight chain or branched), C₁-C₆ alkoxy (straight chain or branched),halogen, —OH, —CF₃, or —OCF₃;

[0020] b) a five-membered saturated, unsaturated or partiallyunsaturated heterocycle containing up to two heteroatoms selected fromthe group consisting of —O—, —NH—, —N(C₁C₄ alkyl)—, —N═, and —S(O)_(m)—,wherein m is an integer of from 0-2, optionally substituted with 1-3substituents independently selected from the group consisting ofhydrogen, hydroxyl, halo, C₁-C₄ alkyl, trihalomethyl, C₁-C₄ alkoxy,trihalomethoxy, C₁-C₄ acyloxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl,C₁-C₄ alkylsulfonyl, hydroxy (C₁-C₄)alkyl, —CO₂H—, —CN—, —CONHR₁—,—NH₂—, C₁-C₄ alkylamino, di(C₁-C₄)alkylamino, —NHSO₂R₁—, —NHCOR₁—, —NO₂,and phenyl optionally substituted with 1-3 (C₁-C₄)alkyl;

[0021] c) a six-membered saturated, unsaturated or partially unsaturatedheterocycle containing up to two heteroatoms selected from the groupconsisting of —O—, —NH—, —N(C₁C₄ alkyl)—, —N═, and —S(O)_(m)—, wherein mis an integer of from 0-2, optionally substituted with 1-3 substituentsindependently selected from the group consisting of hydrogen, hydroxyl,halo, C₁-C₄ alkyl, trihalomethyl, C₁-C₄ alkoxy, trihalomethoxy, C₁-C₄acyloxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl,hydroxy (C₁-C₄)alkyl, —CO₂H—, —CN—, —CONHR₁—, —NH₂—, C₁-C₄ alkylamino,di(C₁-C₄)alkylamino, —NHSO₂R₁—, —NHCOR₁—, —NO₂, and phenyl optionallysubstituted with 1-3 (C₁-C₄)alkyl;

[0022] d) a seven-membered saturated, unsaturated or partiallyunsaturated heterocycle containing up to two heteroatoms selected fromthe group consisting of —O—, —NH—, —N(C₁C₄ alkyl)—, —N═, and —S(O)_(m)—,wherein m is an integer of from 0-2, optionally substituted with 1-3substituents independently selected from the group consisting ofhydrogen, hydroxyl, halo, C₁-C₄ alkyl, trihalomethyl, C₁-C₄ alkoxy,trihalomethoxy, C₁-C₄ acyloxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl,C₁-C₄ alkylsulfonyl, hydroxy (C₁-C₄)alkyl, —CO₂H—, —CN—, —CONHR₁—,—NH₂—, C₁-C₄ alkylamino, di(C₁-C₄)alkylamino, —NHSO₂R₁—, —NHCOR₁—, —NO₂,and phenyl optionally substituted with 1-3 (C₁-C₄)alkyl;; or

[0023] e) a bicyclic heterocycle containing from 6-12 carbon atomseither bridged or fused and containing up to two heteroatoms selectedfrom the group consisting of —O—, —NH—, —N(C₁C₄ alkyl)—, and —S(O)_(m)—,wherein m is an integer of from 0-2, optionally substituted with 1-3substituents independently selected from the group consisting ofhydrogen, hydroxyl, halo, C₁-C₄ alkyl, trihalomethyl, C₁-C₄ alkoxy,trihalomethoxy, C₁-C₄ acyloxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl,C₁-C₄ alkylsulfonyl, hydroxy (C₁-C₄)alkyl, —CO₂H—, —CN—, —CONHR₁—,—NH₂—, C₁-C₄ alkylamino, di(C₁-C₄)alkylamino, —NHSO₂R₁—, —NHCOR₁—, —NO₂,and phenyl optionally substituted with 1-3 (C₁-C₄)alkyl;

[0024] and the pharmaceutically acceptable salts thereof.

[0025] The more preferred compounds of this invention are those havingthe general structures I or II, above, wherein:

[0026] R₁ is selected from H, OH or the C₁-C₁₂ esters or alkyl ethersthereof, benzyloxy, or halogen;

[0027] R₂, R₃, R₅, and R₆ are independently selected from H, OH or theC₁-C₁₂ esters or alkyl ethers thereof, halogen, cyano, C₁-C₆ alkyl, ortrihalomethyl, preferably trifluoromethyl, with the proviso that, whenR₁ is H, R₂ is not OH;

[0028] R₄ is selected from H, OH or the C₁-C₁₂ esters or alkyl ethersthereof, benzyloxy, halogen, cyano, C₁-C₆ alkyl, or trihalomethyl;

[0029] X is selected from H, C₁-C₆ alkyl, cyano, nitro, trifluoromethyl,halogen;

[0030] Y is the moiety

[0031] R₇ and R₈ are selected independently from H, C₁-C₆ alkyl, orcombined by —(CH₂)p—, wherein p is an integer of from 2 to 6, so as toform a ring, the ring being optionally substituted by up to threesubstituents selected from the group of hydrogen, hydroxyl, halo, C₁-C₄alkyl, trihalomethyl, C₁-C₄ alkoxy, trihalomethoxy, C₁-C₄ alkylthio,C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, hydroxy (C₁-C₄)alkyl, —CO₂H,—CN, —CONH(C₁-C₄), —NH₃, C₁-C₄ alkylamino, C₁-C₄ dialkylamino,—NHSO₂(C₁-C₄), —NHCO(C₁-C₄), and —NO₃;

[0032] and the pharmaceutically acceptable salts thereof.

[0033] The rings formed by a concatenated R₇ and R₈, mentioned above,may include, but are not limited to, aziridine, azetidine, pyrrolidine,piperidine, hexamethyleneamine or heptamethyleneamine rings.

[0034] The most preferred compounds of the present invention are thosehaving the structural formulas I or II, above, wherein R₁ is OH; R₂-R₆are as defined above; X is selected from the group of Cl, NO₂, CN, CF₃,or CH₃; and Y is the moiety

[0035] and R₇ and R₈ are concatenated together as —(CH₂)_(r)—, wherein ris an integer of from 4 to 6, to form a ring optionally substituted byup to three substituents selected from the group of hydrogen, hydroxyl,halo, C₁-C₄ alkyl, trihalomethyl, C₁-C₄ alkoxy, trihalomethoxy, C₁-C₄alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, hydroxy(C₁-C₄)alkyl, —CO₂H, —CN, —CONH(C₁-C₄)alkyl, —NH₂, C₁-C₄ alkylamino,di(C₁-C₄)alkylamino, —NHSO₂(C₁-C₄)alkyl, —NHCO(C₁-C₄)alkyl, and —NO₂;

[0036] and the pharmaceutically acceptable salts thereof.

[0037] In another embodiment of this invention, when R₇ and R₈ areconcatenated together as —(CH₂)p—, wherein p is an integer of from 2 to6, preferably 4 to 6, the ring so formed is optionally substituted with1-3 substituents selected from a group containing C₁-C₃ alkyl,trifluoromethyl, halogen, hydrogen, phenyl, nitro, —CN.

[0038] The invention includes sulfate, sulfamates and sulfate esters ofphenolic groups. Sulfates can be readily prepared by the reaction of thefree phenolic compounds with sulfur trioxide complexed with an aminesuch as pyridine, trimethylamine, triethylamine, etc. Sulfamates can beprepared by treating the free phenolic compound with the desired aminoor alkylamino or dialkylamino sulfamyl chloride in the presence of asuitable base such as pyridine. Sulfate esters can be prepared byreaction of the free phenol with the desired alkanesulfonyl chloride inthe presence of a suitable base such as pyridine. Additionally, thisinvention includes compounds containing phosphates at the phenol as wellas dialkyl phosphates. Phosphates can be prepared by reaction of thephenol with the appropriate chlorophosphate. The dialkylphosphates canbe hydrolyzed to yield the free phosphates. Phosphinates are alsoclaimed where the phenol is reacted with the desired dialkylphosphinicchloride to yield the desired dialkylphosphinate of the phenol.

[0039] The invention includes acceptable salt forms formed from theaddition reaction with either inorganic or organic acids. Inorganicacids such as hydrochloric acid, hydrobromic acid, hydroiodic acid,sulfuric acid, phosphoric acid, nitric acid useful as well as organicacids such as acetic acid, propionic acid, citric acid, maleic acid,malic acid, tartaric acid, phthalic acid, succinic acid, methanesulfonicacid, toluenesulfonic acid, napthalenesulfonic acid, camphorsulfonicacid, benzenesulfonic acid are useful. It is known that compoundspossessing a basic nitrogen can be complexed with many different acids(both protic and non-protic) and usually it is preferred to administer acompound of this invention in the form of an acid addition salt.Additionally, this invention includes quaternary ammonium salts of thecompounds herein. These can be prepared by reacting the nucleophilicamines of the side chain with a suitably reactive alkylating agent suchas an alkyl halide or benzyl halide.

[0040] The methods of this invention include the treatment, prevention,alleviation or inhibition of maladies or disorders associated with anexcess of neuropeptide Y in a mammal, preferably in a human. Thesedisorders or maladies include:

[0041] a) disorders of the heart, circulatory vessels and the renalsystem, including heart failure, vasospasm, shock, cardiac hypertrophy,elevated blood pressure, myocardial infarction, angina, arrythmia,peripheral vascular disease, and abnormal renal conditions associatedwith excess neuropeptide Y;

[0042] b) the conditions of increased sympathetic nervous activity, suchas following surgical treatment;

[0043] c) neuropeptide Y-related cerebral diseases and conditions, suchcerebral infarction, epilepsy, neurodegenerative conditions, stroke andrelated conditions, cerebral vasospasm or hemorrhage, anxiety,schizophrenia, depression and dementias;

[0044] d) neuropeptide conditions related to pain or nociception;

[0045] e) neuropeptide Y-associated diseases with abnormalgastrointestinal motility and secretion, such as urinary incontinence,Crohn's disease and the temporary arrest of intestinal peristalsis knownas ileus (including paralytic ileus, adynamic ileus and paresis);

[0046] f) neuropeptide Y-related food and drink disorders, includinganorexia nervosa, bulimia, metabolic disorders and obesity;

[0047] g) neuropeptide Y-associated maladies of sexual dysfunction andreproductive disorders;

[0048] h) inflammatory conditions related to neuropeptide Y;

[0049] i) respiratory conditions, such as asthma and broncoconstriction;

[0050] j) diseases associated with abnormal hormone release, includingleutinizing hormone, growth hormone, insulin and prolactin.

[0051] The present invention includes methods utilizing a first subsetor subgroup of compounds of the formulas IIII or IV, below:

[0052] wherein the variable substituents including R₁, R₂, R₃, R₄, R₅,R₆, n, X, and Y are as defined above, or a pharmaceutically acceptablesalt thereof.

[0053] The more preferred compounds of this first subset of compoundsare those having the general structures III or IV, above, wherein:

[0054] R₁ is selected from H, OH or the C₁-C₁₂ esters or alkyl ethersthereof, benzyloxy, or halogen;

[0055] R₂, R₃, R₅, and R₆ are independently selected from H, OH or theC₁-C₁₂ esters or alkyl ethers thereof, halogen, cyano, C₁-C₆ alkyl, ortrihalomethyl, preferably trifluoromethyl, with the proviso that, whenR₁ is H, R₂ is not OH;

[0056] R₄ is selected from H, OH or the C₁-C₁₂ esters or alkyl ethersthereof, benzyloxy, halogen, cyano, C₁-C₆ alkyl, or trihalomethyl;

[0057] X is selected from H, C₁-C₆ alkyl, cyano, nitro, trifluoromethyl,halogen;

[0058] Y is the moiety

[0059] R₇ and R₈ are selected independently from H, C₁-C₆ alkyl, orcombined by —(CH₂)p—, wherein p is an integer of from 2 to 6, so as toform a ring, the ring being optionally substituted by up to threesubstituents selected from the group of hydrogen, hydroxyl, halo, C₁-C₄alkyl, trihalomethyl, C₁-C₄ alkoxy, trihalomethoxy, C₁-C₄ alkylthio,C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, hydroxy (C₁-C₄)alkyl, —CO₂H,—CN, —CONH(C₁-C₄), —NH₃, C₁-C₄ alkylamino, C₁-C₄ dialkylamino,—NHSO₂(C₁-C₄), —NHCO(C₁-C₄), and —NO₃;

[0060] and the pharmaceutically acceptable salts thereof.

[0061] The rings formed by a concatenated R₇ and R₈, mentioned above,may include, but are not limited to, aziridine, azetidine, pyrrolidine,piperidine, hexamethyleneamine or heptamethyleneamine rings.

[0062] The most preferred compounds of this first subset of compoundsare those having the structural formulas I or II, above, wherein R₁ isOH; R₂-R₆ are as defined above; X is selected from the group of Cl, NO₂,CN, CF₃, or CH₃; and Y is the moiety

[0063] and R₇ and R₈ are concatenated together as —(CH₂)_(r)—, wherein ris an integer of from 4 to 6, to form a ring optionally substituted byup to three substituents selected from the group of hydrogen, hydroxyl,halo, 0₁-C₄ alkyl, trihalomethyl, C₁-C₄ alkoxy, trihalomethoxy, C₁-C₄alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, hydroxy(C₁-C₄)alkyl, —CO₂H, —CN, —CONH(C₁-C₄)alkyl, —NH₂, C₁-C₄ alkylamino,di(C₁-C₄)alkylamino, —NHSO₂(C₁-C₄)alkyl, —NHCO(C₁-C₄)alkyl, and —NO₂;

[0064] and the pharmaceutically acceptable salts thereof.

[0065] In another embodiment of this first subset of compounds, when R₇and R₈ are concatenated together as —(CH₂)p—, wherein p is an integer offrom 2 to 6, preferably 4 to 6, the ring so formed is optionallysubstituted with 1-3 substituents selected from a group containing C₁-C₃alkyl, trifluoromethyl, halogen, hydrogen, phenyl, nitro, —CN.

[0066] Among the preferred compounds of this first subset of compoundsare the following:

[0067]5-Benzyloxy-2-(4-ethoxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indole;

[0068]5-Benzyloxy-2-phenyl-3-methyl-1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-1H-indole;

[0069]5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-1H-indole;

[0070]5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1-[4-(2-diisopropylamino-1-yl-ethoxy)-benzyl]-1H-indole;

[0071]5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1-[4-(2-butyl-methylamino-1-ylethoxy)-benzyl]-1H-indole;

[0072]5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1-{4-dimethylamino)-ethoxy]-benzyl}-1H-indole;

[0073]5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1-{4-[2-(2-methyl-piperidin-1-yl)-ethoxy]-benzyl}-1H-indole;

[0074]5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1-{4-[2-(3-methyl-piperidin-1-yl)-ethoxy]-benzyl}-1H-indole;

[0075]5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1-{4-[2-(4-methyl-piperidin-1-yl)-ethoxy]-benzyl}-1H-indole;

[0076]5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1{4-[2-((cis)-2,6-Dimethyl-piperidin-1-yl)-ethoxy]-benzyl}-1H-indole;

[0077]5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-{4-[2-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-ethoxy]-benzyl}-1H-indole;

[0078](1S,4R)-5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl{4-[2-(2-Aza-bicyclo[2.2.1]hept-2-yl)-ethoxy]-benzyl}-1H-indole;

[0079]5-Benzyloxy-2-(4-flouro-phenyl)-3-methyl-1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-1H-indole;

[0080]5-Benzyloxy-2-(4-flouro-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indole;

[0081]5-Benzyloxy-2-(4-chloro-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indole;

[0082]5-Benzyloxy-2-[3,4-methylenedioxy-phenyl]-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indole;

[0083]5-Benzyloxy-2-[4-isopropoxy-phenyl]-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indole;

[0084]5-Benzyloxy-2-[4-methyl-phenyl]-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indole;

[0085]1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-5-benzyloxy-2-(3-benzyloxy-phenyl)-3-methyl-1H-indole;

[0086]5-Benzyloxy-2-(4-benzyloxy-3-fluoro-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indole;

[0087]5-Benzyloxy-2-(4-benzyloxy-3-fluoro-phenyl)-3-methyl-1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-1H-indole;

[0088]5-Benzyloxy-2-(3-methoxy-phenyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-3-methyl-1H-indole;

[0089]5-Benzyloxy-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-2-(4-trifluoromethoxy-phenyl)-1H-indole;

[0090](2-{4-[5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-indol-1-ylmethyl]-phenoxy}-ethyl)-cyclohexyl-amine;

[0091]5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1-{4-methylpiperazin-1-yl)-ethoxy]-benzyl}-1H-indole;

[0092]1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-5-benzyloxy-2-(3-methoxy-phenyl)-3-methyl-1H-indole;

[0093] 4-{3-Methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indole};

[0094]4-{3-Methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-2-yl}-phenol;

[0095]3-Methyl-2-phenyl-1-[4-(2-piperidine-1-yl-ethoxy)-benzyl]-1H-indol-5-ol;

[0096]4-{5-Methoxy-3-methyl-1-{4-[2-(piperidin-1-yl)-ethoxy]-benzyl}-1H-indol-2-yl}-phenol;

[0097]2-(4-methoxy-phenyl)-3-methyl-1-{4-[2-(piperidin-1-yl)-ethoxy]-benzyl}-1H-indol-5-ol;

[0098]5-Methoxy-2-(4-methoxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indole;

[0099]1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-5-methoxy-2-(4-methoxy-phenyl)-3-methyl-1H-indole;

[0100]2-(4-Ethoxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol;

[0101]1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(4-ethoxy-phenyl)-3-methyl-1H-indol-5-ol;

[0102]4-{5-Fluoro-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-2-yl}-phenol;

[0103]1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-3-methyl-2-phenyl-1H-indol-5-ol;

[0104]2-(4-Hydroxy-phenyl)-3-methyl-1-[4-(2-pyrollidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol;

[0105]1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-indol-5-ol;

[0106]1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-indol-5-ol;

[0107]1-[4-(2-Azocan-1-yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-indol-5-ol;

[0108]2-(4-Hydroxy-phenyl)-3-methyl-1-[4-(2-dimethyl-1-yl-ethoxy)-benzyl]-1H-indol-5-ol;

[0109]2-(4-Hydroxy-phenyl)-3-methyl-1-[4-(2-diethyl-1-yl-ethoxy)-benzyl]-1H-indol-5-ol;

[0110]1-[4-(2-Dipropylamino-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-indol-5-ol;

[0111]1-[4-(2-Dibutylamino-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-indol-5-ol;

[0112]1-[4-(2-Diisopropylamino-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-indol-5-ol;

[0113]1-{4-[2-(Butyl-methyl-amino)-ethoxy]-benzyl-2-(4-hydroxy-phenyl)-3-methyl-1H-indol-5-ol;

[0114]2-(4-Hydroxy-phenyl)-3-methyl-1-{4-[2-(2-methyl-piperidin-1-yl)-ethoxy]-benzyl}-1H-indol-5-ol;

[0115]2-(4-Hydroxy-phenyl)-3-methyl-1-[4-[2-(3-methyl-piperdin-1-yl)-ethoxy]-benzyl}-1H-indol-5-ol;

[0116]2-(4-Hydroxy-phenyl)-3-methyl-1-{4-[2-(4-methyl-piperidin-1-yl)-ethoxy]-benzyl}-1H-indol-5-ol;

[0117]1-{4-[2-(3,3-Dimethyl-piperidin-1-yl)-ethoxy]-benzyl}-2-(4-hydroxy-phenyl)-3-methyl-1H-indol-5-ol;

[0118]1-{4-[2-((cis)-2,6-Dimethyl-piperidin-1-yl)-ethoxy]-benzyl}-2-(4-hydroxy-phenyl)-3-methyl-1H-indol-5-ol;

[0119]2-(4-Hydroxy-phenyl)-1-{4-[2-(4-hydroxy-piperidin-1-yl)-ethoxy]-benzyl}-3-methyl-1H-indol-5-ol;

[0120] (1S,4R)-1-{4-[2-(2-Aza-bicyclo[2.2.1]hept-2-yl)-ethoxy]-benzyl}-2-(4-hydroxy-phenyl)-3-methyl-1H-indol-5-ol;

[0121]2-(4-Hydroxy-phenyl)-3-methyl-1-{4-[2-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-ethoxy]-benzyl}-1H-indol-5-ol;

[0122]2-(4-Fluoro-phenyl)-3-methyl-1-[4-(2-piperidine-1-yl-ethoxy)-benzyl]-1H-indol-5-ol;

[0123]1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(4-fluoro-phenyl)-3-methyl-1H-indol-5-ol;

[0124]2-(3-Methoxy-4-hydroxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol;

[0125]2-Benzo[1,3]dioxol-5-yl-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol;

[0126]2-(4-Isopropoxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol;

[0127]1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(4-isopropoxy-phenyl)-3-methyl-1H-indol-5-ol;

[0128]2-(4-Cyclopenyloxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol;

[0129]3-Methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-2-(4-trifluoromethyl-phenyl)-1H-indol-5-ol;

[0130]3-Methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-2-p-tolyl-1H-indol-5-ol;

[0131]2-(4-Chloro-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol;

[0132]2-(2,4-Dimethoxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol;

[0133]2-(3-Hydroxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol;

[0134]1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(3-hydroxy-phenyl)-3-methyl-1H-indole-5-ol;

[0135]2-(3-Fluoro-4-hydroxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol;

[0136]2-(3-Fluoro-4-hydroxy-phenyl)-3-methyl-1-[4-(azepan-1-yl-ethoxy)-benzyl]-1H-indol-5-ol;

[0137]2-(3-Methoxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indole-5-ol;

[0138]3-Methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-2-(4-trifluoromethoxy-phenyl)-1H-indole-5-ol;

[0139]3-Chloro-2-(4-hydroxy-phenyl)-1-[4-(2-pyrrolidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol;

[0140]3-Chloro-2-(4-hydroxy-phenyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol;

[0141]3-Chloro-2-(4-hydroxy-phenyl)-1-4-(2-azepan-1-yl-ethoxy)-benzyl]-1H-indol-5-ol;

[0142]3-Chloro-2-(4-hydroxy-2-methyl-phenyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl ]-1H-indol-5-ol;

[0143]2-(4-Hydroxy-phenyl)-3-ethyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol;

[0144]5-Hydroxy-2-(4-Hydroxy-phenyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indole-3-carbonitrile;

[0145]1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-5-hydroxy-2-(4-hydroxy-phenyl)-1H-indole-3-cabonitrile;

[0146]5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-chloro-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indole;

[0147]5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-chloro-1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-1H-indole;

[0148]5-Benzyloxy-2-(2-methyl-4-benzyloxy-phenyl)-3-chloro-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indole;

[0149]5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-ethyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indole;

[0150]5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-cyano-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indole;

[0151]5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-cyano-1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-1H-indole;

[0152] Di-propionate of1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-indol-5-ol;

[0153] Di-pivalate of1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-indol-5-ol;

[0154]5-Benzyloxy-2-(4-benzyloxy-phenyl)-1-[4-(3-piperidin-1-yl-propoxy)-benzyl]-3-methyl-1H-indole;

[0155]2-(4-Hydroxy-phenyl)-3-methyl-1-{4-[3-(piperidin-1-yl)-propoxy]-benzyl}-1H-indol-5-ol;

[0156]2-(4-Hydroxy-phenyl)-1-[3-methoxy-4-(2-piperidin-1-yl-ethoxy)-benzyl]-3-methyl-1H-indol-5-ol;

[0157]2-(4-Hydroxy-phenyl)-1-[3-methoxy-4-(2-azepan-1-yl-ethoxy)-benzyl]-3-methyl-1H-indol-5-ol;

[0158]5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1-[3-Methoxy-4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indole;

[0159]5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1-[2-Methoxy-4-(2-azepan-1-yl-ethoxy)-benzyl]-1H-indole;

[0160]2-(4-Hydroxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol;

[0161] or the pharmaceutically acceptable salts thereof.

[0162] The compounds of this first subset or subgroup of compounds canbe produced by the methods described in EP 0 802 183 A1, published Oct.22, 1997, and U.S. Pat. No. 5,780,497, the subject matter of which isincorporated herein by reference, or by other methods known in the art.Aryloxy-alkyl-dialkylamines or aryloxy-alkyl-cyclic amines useful asintermediates in the production of the compounds above can be producedand used as disclosed in WO 99/19293, published Apr. 22, 1999, thesubject matter of which is also incorporated herein by reference.

[0163] A second subset or subgroup of compounds useful with thisinvention includes those of formulas (V) or (VI), below:

[0164] wherein the variable substituents including R₁, R₂, R₃, R₄, R₅,R₆, n, X, and Y are as defined above, or a pharmaceutically acceptablesalt thereof.

[0165] Among the preferred compounds of this second subset or subgroupare the following:

[0166](E)-N,N-Diethyl-3-{4-[5-hydroxy-2-(4-hydroxy-phenyl)-3-methyl-indol-1-ylmethyl]-phenyl}-acrylamide;

[0167]1(E)-N-tert-butyl-3-{4-[5-hydroxy-2-(4-hydroxy-phenyl)-3-methyl-indol-1-ylmethyl]-phenyl}-acrylamide;

[0168](E)-Pyrollidino-3-{4-[5-hydroxy-2-(4-hydroxy-phenyl)-3-methyl-indol-1-ylmethyl]-phenyl}-acrylamide;

[0169](E)-N,N-Dimethyl-3-{4-[5-hydroxy-2-(4-hydroxy-phenyl)-3-methyl-indol-1-ylmethyl]-phenyl}-acrylamide;

[0170](E)-N,N-Dibutyl-3-{4-[5-hydroxy-2-(4-hydroxy-phenyl)-3-methyl-indol-1-ylmethyl]-phenyl}-acrylamide;

[0171](E)-N-Butyl,N′-methyl-3-{4-[5-hydroxy-2-(4-hydroxy-phenyl)-3-methyl-indol-1-ylmethyl]-phenyl}-acrylamide;

[0172](E)-Morpholinino-3-{4-[5-hydroxy-2-(4-hydroxy-phenyl)-3-methyl-indol-1-ylmethyl]-phenyl}-acrylamide;

[0173](E)-3-{4-[5-hydroxy-2-(4-hydroxy-phenyl)-3-methyl-indol-1-ylmethyl]-phenyl}-acrylamide;

[0174](E)-N,Methyl-3-{4-[5-hydroxy-2-(4-hydroxy-phenyl)-3-methyl-indol-1-ylmethyl]-phenyl}-acrylamide;

[0175](E)-N,N-Dibutyl-3-{4-[5-hydroxy-2-(4-fluoro-phenyl)-3-methyl-indol-1-ylmethyl]-phenyl}-acrylamide;

[0176](E)-N-Butyl,N′-Methyl-3-{4-[5-hydroxy-2-(4-fluoro-phenyl)-3-methyl-indol-1-ylmethyl]-phenyl}-acrylamide;

[0177] as well as the pharmaceutically acceptable salts and estersthereof.

[0178] The compounds of this second subset or subgroup of compounds canbe produced by the methods described in EP 0 802 184 A1, published Oct.22, 1997, which is incorporated herein by reference, or by other methodsknown in the art.

[0179] A third subset of compounds useful with the present inventioninclude those of the formulae VII and VIII:

[0180] wherein n is 1, 2 or 3 and the variable substituents includingR₁, R₂, R₃, R₄, R₅, R₆, n, X, and Y are as defined above, or apharmaceutically acceptable salt thereof.

[0181] Among the preferred compounds of this third subset are:

[0182] 2-(4-Hydroxy-phenyl)-3-methyl-1-[4-(3-N, N-dimethyl-1-yl-prop-1-ynyl)-benzyl]-1H-indol-5-ol;

[0183]2-(4-Hydroxy-phenyl)-3-methyl-1-[4-(3-piperidin-1-yl-prop-1-ynyl)-benzyl]-1H-indol-5-ol;and

[0184]2-(4-Hydroxy-phenyl)-3-methyl-1-[4-(3-pyrrolidin-1-yl-prop-1-ynyl)-benzyl]-1H-indol-5-ol;

[0185] or pharmaceutically acceptable salts or esters thereof.

[0186] The compounds of this third subset or subgroup of compounds canbe produced by the methods described in U.S. Pat. No. 5,880,137 (Milleret al.), which is incorporated herein by reference, or by other methodsknown in the art.

[0187] Within each of the first, second and third subsets of compoundsof this invention are further subdivisions of more preferred compoundshaving the general structures I through VIII, above, wherein:

[0188] R₁ is selected from H, OH or the C₁-C₁₂ esters or alkyl ethersthereof, halogen;

[0189] R₂, R₃, R₄, R₅, and R₆ are independently selected from H, OH orthe C₁-C₁₂ esters or alkyl ethers thereof, halogen, cyano, C₁-C₆ alkyl,or trihalomethyl, preferably trifluoromethyl, with the proviso that,when R₁ is H, R₂ is not OH;

[0190] X is selected from H, C₁-C₆ alkyl, cyano, nitro, trifluoromethyl,halogen;

[0191] Y is the moiety

[0192] R₇ and R₈ are selected independently from H, C₁-C₆ alkyl, orcombined by —(CH₂)p—, wherein p is an integer of from 2 to 6, so as toform a ring, the ring being optionally substituted by up to threesubstituents selected from the group of hydrogen, hydroxyl, halo, C₁-C₄alkyl, trihalomethyl, C₁-C₄ alkoxy, trihalomethoxy, C₁-C₄ alkylthio,C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, hydroxy (C₁-C₄)alkyl, —CO₂H,—CN, —CONH(C₁-C₄), —NH₃, C₁-C₄ alkylamino, C₁-C₄ dialkylamino,—NHSO₂(C₁-C₄), —NHCO(C₁-C₄), and —NO₃;

[0193] and the pharmaceutically acceptable salts thereof.

[0194] The rings formed by a concatenated R₇ and R₈, mentioned above,may include, but are not limited to, aziridine, azetidine, pyrrolidine,piperidine, hexamethyleneamine or heptamethyleneamine rings.

[0195] The most preferred compounds of the present invention are thosehaving the structural formulas I through VIII, above, wherein R₁ is OH;R₂-R₆ are as defined above; X is selected from the group of Cl, NO₂, CN,CF₃, or CH₃; and Y is the moiety

[0196] and R₇ and R₈ are concatenated together as —(CH₂)_(r)—, wherein ris an integer of from 4 to 6, to form a ring optionally substituted byup to three substituents selected from the group of hydrogen, hydroxyl,halo, C₁-C₄ alkyl, trihalomethyl, C₁-C₄ alkoxy, trihalomethoxy, C₁-C₄alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, hydroxy(C₁-C₄)alkyl, —CO₂H, —CN, —CONH(C₁-C₄)alkyl, —NH₂, C₁-C₄ alkylamino,di(C₁-C₄)alkylamino, —NHSO₂(C₁-C₄)alkyl, —NHCO(C₁-C₄)alkyl, and —NO₂;

[0197] and the pharmaceutically acceptable salts thereof.

[0198] In another embodiment of this invention, when R₇ and R₈ areconcatenated together as —(CH₂)p—, wherein p is an integer of from 2 to6, preferably 4 to 6, the ring so formed is optionally substituted with1-3 substituents selected from a group containing C₁-C₃ alkyl,trifluoromethyl, halogen, hydrogen, phenyl, nitro, —CN.

[0199] Among the preferred compounds for use as active ingredients inthe formulations and methods of this invention are1-[4-(2-Azepan-1yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-indol-5-ol,also known as TSE-424, and2-(4-Hydroxy-phenyl)-3-methyl-1-(4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol,also known as ERA-923, as well as pharmaceutically acceptable salt formsof these compounds.

[0200] The invention includes sulfate, sulfamates and sulfate esters ofphenolic groups. Sulfates can be readily prepared by the reaction of thefree phenolic compounds with sulfur trioxide complexed with an aminesuch as pyridine, trimethylamine, triethylamine, etc. Sulfamates can beprepared by treating the free phenolic compound with the desired aminoor alkylamino or dialkylamino sulfamyl chloride in the presence of asuitable base such as pyridine. Sulfate esters can be prepared byreaction of the free phenol with the desired alkanesulfonyl chloride inthe presence of a suitable base such as pyridine. Additionally, thisinvention includes compounds containing phosphates at the phenol as wellas dialkyl phosphates. Phosphates can be prepared by reaction of thephenol with the appropriate chlorophosphate. The dialkylphosphates canbe hydrolyzed to yield the free phosphates. Phosphinates are alsoclaimed where the phenol is reacted with the desired dialkylphosphinicchloride to yield the desired dialkylphosphinate of the phenol.

[0201] The invention includes acceptable salt forms formed from theaddition reaction with either inorganic or organic acids. Inorganicacids such as hydrochloric acid, hydrobromic acid, hydroiodic acid,sulfuric acid, phosphoric acid, nitric acid useful as well as organicacids such as acetic acid, propionic acid, citric acid, maleic acid,malic acid, tartaric acid, phthalic acid, succinic acid, methanesulfonicacid, toluenesulfonic acid, napthalenesulfonic acid, camphorsulfonicacid, benzenesulfonic acid are useful. It is known that compoundspossessing a basic nitrogen can be complexed with many different acids(both protic and non-protic) and usually it is preferred to administer acompound of this invention in the form of an acid addition salt.Additionally, this invention includes quaternary ammonium salts of thecompounds herein. These can be prepared by reacting the nucleophilicamines of the side chain with a suitably reactive alkylating agent suchas an alkyl halide or benzyl halide.

[0202] It is understood that the dosage, regimen and mode ofadministration of these compounds will vary according to the malady andthe individual being treated and will be subject to the judgement of themedical practitioner involved. It is preferred that the administrationof one or more of the compounds herein begin at a low dose and beincreased until the desired effects are achieved.

[0203] Effective administration of these compounds may be given at aneffective dose of from about 0.1 mg/day to about 500 mg/day. Preferably,administration will be from about 1 mg/day to about 200 mg/day in asingle dose or in two or more divided doses. Such doses may beadministered in any manner useful in directing the active compoundsherein to the recipient's bloodstream, including orally, parenterally(including intravenous, intraperitoneal and subcutaneous injections),and transdermally. For the purposes of this disclosure, transdermaladministrations are understood to include all administrations across thesurface of the body and the inner linings of bodily passages includingepithelial and mucosal tissues. Such administrations may be carried outusing the present compounds, or pharmaceutically acceptable saltsthereof, in lotions, creams, foams, patches, suspensions, solutions, andsuppositories (rectal and vaginal).

[0204] When the active ingredient in the formulations and methods ofthis invention is1-[4-(2-Azepan-1yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-indol-5-ol,also known as TSE-424, or a pharmaceutically acceptable salt thereof,the preferred daily dosage for oral delivery is from about 0.1 to about50 mg, preferably from about 2.5 to about 40 mg per day.

[0205] When the active ingredient in the formulations and methods ofthis invention is2-(4-Hydroxy-phenyl)-3-methyl-1-(4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol,also known as ERA-923, or a pharmaceutically acceptable salt formthereof, the preferred daily dosage for oral delivery is from about 0.1to about 200 mg, preferably from about 2.5 to about 100 mg per day.

[0206] Oral formulations containing the active compounds of thisinvention may comprise any conventionally used oral forms, includingtablets, capsules, buccal forms, troches, lozenges and oral liquids,suspensions or solutions. Capsules may contain mixtures of the activecompound(s) with inert fillers and/or diluents such as thepharmaceutically acceptable starches (e.g. corn, potato or tapiocastarch), sugars, artificial sweetening agents, powdered celluloses, suchas crystalline and microcrystalline celluloses, flours, gelatins, gums,etc. Useful tablet formulations may be made by conventional compression,wet granulation or dry granulation methods and utilize pharmaceuticallyacceptable diluents, binding agents, lubricants, disintegrants,suspending or stabilizing agents, including, but not limited to,magnesium stearate, stearic acid, talc, sodium lauryl sulfate,microcrystalline cellulose, carboxymethylcellulose calcium,polyvinylpyrrolidone, gelatin, alginic acid, acacia gum, , xanthan gum,sodium citrate, complex silicates, calcium carbonate, glycine, dextrin,sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose,kaolin, mannitol, sodium chloride, talc, dry starches and powderedsugar. Oral formulations herein may utilize standard delay or timerelease formulations to alter the absorption of the active compound(s).Suppository formulations may be made from traditional materials,including cocoa butter, with or without the addition of waxes to alterthe suppository's melting point, and glycerin. Water soluble suppositorybases, such as polyethylene glycols of various molecular weights, mayalso be used.

[0207] Solid oral formulations, preferably in the form of a film coatedtablet or capsule, useful for this invention include the activepharmacological agents disclosed herein in combination with carrier orexcipient systems having the components:

[0208] a) a filler and disintegrant component comprising from about 5%to about 82% by weight (wght) of the total formulation, preferablybetween about 30% and about 80% of the formulation, of which from about4% to about 40% by weight of the total formulation comprises one or morepharmaceutically acceptable disintegrants;

[0209] b) optionally, a wetting agent comprising from about 0.2 to about5% of the composition (wght), such as selected from the group of sodiumlauryl sulfate, polyoxyethylene sorbitan fatty acid esters,polyoxyethylene alkyl ethers, sorbitan fatty acid esters, polyethyleneglycols, polyoxyethylene castor oil derivatives, docusate sodium,quaternary ammonium compounds, sugar esters of fatty acids andglycerides of fatty acids;

[0210] c) a lubricant comprising from about 0.2% to about 10% of thecomposition (wght), such as selected from the group of magnesiumstearate or other metallic stearates (e.g. calcium stearate or zincstearate), fatty acid esters (e.g. sodium stearyl fumarate), fatty acids(e.g. stearic acid), fatty alcohols, glyceryl behenate, mineral oil,parrafins, hydrogenated vegetable oils, leucine, polyethylene glycols,metallic lauryl sulfates and sodium chloride; and

[0211] d) optionally, a glidant comprising from about 0.1% to about 10%(wght) of the composition, the glidant selected from those known in theart, including from the group of silicon dioxide, talc, metallicstearates, calcium silicate, or metallic lauryl sulfates.

[0212] While the formulations described herein may be used in anuncoated or non-encapsulated solid form, preferably the finalcompositions are coated or encapsulated. The pharmacologicalcompositions may be optionally coated with a film coating, preferablycomprising from about 0.3% to about 8% by weight of the overallcomposition. Film coatings useful with the present formulations areknown in the art and generally consist of a polymer (usually acellulosic type of polymer), a colorant and a plasticizer. Additionalingredients such as wetting agents, sugars, flavors, oils and lubricantsmay be included in film coating formulations to impart certaincharacteristics to the film coat. The compositions and formulationsherein may also be combined and processed as a solid, then placed in acapsule form, such as a gelatin capsule.

[0213] The filler component listed above may utilize the filler orbinder components known in the art for solid oral formulations.Pharmaceutically acceptable fillers or binding agents selected fromthose known in the art including, but not limited to, lactose,microcrystalline cellulose, sucrose, mannitol, calcium phosphate,calcium carbonate, powdered cellulose, maltodextrin, sorbitol, starch,or xylitol.

[0214] In conjunction with or in place of the materials listed above forthe filler component, the present formulations utilize disintegrantagents. These disintegrants may be selected from those known in the art,including pregelatinized starch and sodium starch glycolate. Otheruseful disintegrants include croscarmellose sodium, crospovidone,starch, alginic acid, sodium alginate, clays (e.g. veegum or xanthangum), cellulose floc, ion exchange resins, or effervescent systems, suchas those utilizing food acids (such as citric acid, tartaric acid, malicacid, fumaric acid, lactic acid, adipic acid, ascorbic acid, asparticacid, erythorbic acid, glutamic acid, and succinic acid) and an alkalinecarbonate component (such as sodium bicarbonate, calcium carbonate,magnesium carbonate, potassium carbonate, ammonium carbonate, etc.). Thedisintegrant(s) useful herein will comprise from about 4% to about 40%of the composition by weight, preferably from about 15% to about 35%,more preferably from about 20% to about 35%. Some components may havemultiple functions in the formulations of this invention, acting e.g. asboth a filler and a disintegrant, such a component may be referred to asa filler disintegrant and its function in a specific formulation may besingular even though its properties may allow multiple functionality.

[0215] The pharmaceutical formulations and carrier or excipient systemsherein preferably also contain an antioxidant or a mixture ofantioxidants, most preferably ascorbic acid. Other antioxidants whichmay be used include sodium ascorbate and ascorbyl palmitate, preferablyin conjunction with an amount of ascorbic acid. A preferable range forthe antioxidant(s) is from about 0.5% to about 15% by weight, mostpreferably from about 0.5% to about 5% by weight.

[0216] Among the formulations of this invention are pharmaceuticalformulations containing a pharmaceutically effective amount of an activepharmacological agent and a carrier or excipient system comprising:

[0217] a) a filler and disintegrant component comprising between about50% and about 87% of the formulation, with from about 4% to about 40% ofthe formulation comprising one or more disintegrant agents;

[0218] b) a wetting agent comprising between about 0.5% and about 2.7%of the formulation;

[0219] c) a lubricant comprising between about 0.2% and about 5.5% ofthe formulation; and

[0220] d) a glidant comprising between about 0.1% and about 5.5% of theformulation.

[0221] The percentages listed in the formulations above indicatepercentages by weight of the total weight of the components listed froma) to d). The formulations above also preferably contain an optionalantioxidant component, preferably ascorbic acid, at a concentration offrom about 0.5% to about 5.5% by weight of the formulation. Theformulations are also preferably contained within a pharmaceuticallyacceptable capsule, such as a gel capsule, or coated with a film coatingcomprising from about 0.3% to about 8% by weight of the formulation.

[0222] This invention also comprises a pharmaceutical carrier orexcipient systems useful in pharmaceutical compositions utilizing as anactive ingredient one or more of the compounds described herein, or apharmaceutically acceptable salt thereof, as described herein. Thesepharmaceutical carrier or excipient systems comprise, by weight:

[0223] a) a filler and disintegrant component comprising between about54% and about 80% of the formulation, with the disintegrant agent(s)therein comprising from about 4% to about 40% by weight of the overallformulation;

[0224] b) a wetting agent comprising between about 0.55% and about 2.5%of the formulation;

[0225] c) a lubricant comprising between about 0.2% and about 5.5% ofthe formulation; and

[0226] d) a glidant comprising between about 0.1% and about 5.0% of theformulation.

[0227] The more preferred carrier or excipient systems above alsooptionally and preferably contain an antioxidant component, preferablyascorbic acid, at a concentration of from about 0.1% to about 5.0% byweight.

[0228] Among the carrier or excipient systems of this invention arethose comprising:

[0229] a) a filler and disintegrant component, as described above,comprising between about 50% and about 87% of the formulation, thedisintegrant(s) therein comprising from about 25% to about 35% of theformulation, by weight;

[0230] b) a wetting agent comprising between about 0.55% and about 2.7%of the formulation;

[0231] c) a lubricant comprising between about 0.2% and about 5.5% ofthe formulation;

[0232] d) a glidant comprising between about 0.1% and about 5.5% of theformulation; and

[0233] e) an antioxidant component, preferably ascorbic acid, at aconcentration of from about 0.1% to about 5.5% by weight.

EXAMPLE 1 TSE-424 Acetate—Rapid Dissolution Formulations

[0234] without with Ascorbic Ascorbic Ingredient Acid Acid TSE-424acetate, 10.00 10.00 micronized* Lactose NF fast flow 33.10 31.60Microcrystalline 25.00 25.00 Cellulose, NF (Avicel PH101) Starch 150020.00 20.00 Sodium Lauryl Sulfate  1.50  1.50 NF Sodium Starch Glycolate10.00 10.00 Ascorbic Acid USP — 1.5 Syloid 244 FP  0.15  0.15 MagnesiumStearate  0.25  0.25

[0235] The formulations given above in Table 1 were prepared byincorporating a portion of the excipients in the granulation and aportion is also added in the final blending steps as dry powders. Adissolution profile generated for the formulations demonstrated almost90% release of the drug in 30 minutes. Thus, the unique combination ofdisintegrants and soluble diluents plus the incorporation of bothgranulated and powdered solids into the composition ensures the fastestrelease of drug.

[0236] Wet granulation of the formulations as described in Table 1 maybe carried out by mixing the drug and ascorbic acid with a portion ofthe lactose, microcrystalline cellulose, pregelatinized starch andsodium starch glycolate. The sodium lauryl sulfate is dissolved in thewater and used to granulate the mixture of powders in a high shearmixer. The granulation is dried in a fluid bed dryer to a moisture of2-3%. The particle size of the dried granulation is controlled bypassing through a mill equipped with knife-edged blades and using a 20-or 30-mesh screen. The silicon dioxide and remaining lactose,microcrystalline cellulose, pregelatinized starch, and sodium starchglycolate are mixed with the milled granulation in a tumble-type mixer.The final blend is prepared by adding magnesium stearate to thetumble-type mixer and mixing. Compression is carried out on a rotarytablet press using appropriate size tooling. Coating is performed inconventional coating pans and applying the coating suspension to achievea suitable film coat.

EXAMPLE 2 Modified TSE-424 Formulation

[0237] % w/w 5% Ingredient granulation TSE-424 acetate, micronized^(a)5.00 Lactose NF 41.00 Microcrystalline Cellulose, NF 35.00Pregelatinized Starch NF 10.00 Sodium Lauryl Sulfate NF 1.50 I-AscorbicAcid USP 1.50 Sodium Starch Glycolate NF 5.50 Magnesium Stearate NF 0.50Pur. Water USP^(b) qs

EXAMPLE 3 ERA-923 Formulations

[0238] % w/w 10.86% 11.19% 17.5% 17.9% granu- granu- granu- granu-Ingredient lation lation lation lation ERA-923, micronized^(a) 10.86711.193 17.489 17.909 Lactose NF 29.000 29.000 17.380 18.000Microcrystalline Cellulose, 40.633 42.807 38.000 39.090 NFPregelatinized Starch NF 10.000 10.000 14.630 15.000 Sodium LaurylSulfate NF  2.500 —  2.500 — I-Ascorbic Acid USP  1.500  1.500  1.500 1.500 Sodium Starch Glycolate NF  5.000  5.000  8.000  8.000 MagnesiumStearate NF  0.500  0.500  0.500  0.500 Pur. Water USP^(b) qs qs qs qs

EXAMPLE 4 TSE-424 at 5% Granulation

[0239] A preferred carrier or excipient system for formulating agranulation of from about 2 to about 8% by weight of one of the activepharmacological agents of this invention, preferably about 5%, may beproduced utilizing the carrier or excipient components on a weightpercentage; lactose from about 32% to about 38%, microcrystallinecellulose from about 32% to about 38%, pregelatinized starch from about12% to about 16%, ascorbic acid from about 1% to about 2%, sodium laurylsulfate from about 1% to about 2%, sodium starch glycolate from about 4%to about 8%, silicon dioxide from about 0.1% to about 0.2% and magnesiumstearate from about 0.3% to about 0.7%.

[0240] A formulation of this invention utilizing TSE-424 as the activeingredient at a 5% granulation was prepared utilizing the componentslisted below in a granulation part of components and a dry part. ItemNo. Ingredients Mg/Unit Granulation Part: 1 TSE-424 acetate  5.00 2Lactose NF 26.60 3 Microcrystalline Cellulose NF 25.00 4 PregelatinizedStarch NF 10.00 5 Ascorbic Acid USP  1.50 6 Sodium Lauryl Sulfate NF 1.50 7 Sodium Starch Glycolate NF  4.00 8 Water, Purified USP Q.S.73.60 Dry Part: 9 Lactose NF (fast flo)  9.75 10  MicrocrystallineCellulose NF 10.00 11  Pregelatinized Starch NF  4.00 12  Sodium StarchGlycolate NF  2.00 13  Silicon Dioxide NF  0.15 14  Magnesium StearateNF  0.50 100.00 

[0241] A film coat of White Opadry I (YS-1-18027-A) was applied to thetablets, which were compressed as follows: mg of film coat Dose ofTSE-424 tablet weight, mg applied/tablet  5 mg 100 6.0 10 mg 200 8.0 20mg 400 13.0 

What is claimed:
 1. A method for treatment of diseases associated withan excess of neuropeptide Y in a mammal, the method comprisingadministering to a mammal in need thereof a pharmaceutically effectiveamount of a compound of the formulae I or II:

wherein Z is a moiety selected from the group of:

wherein: R₁ is selected from H, OH or the C₁-C₁₂ esters or C₁-C₁₂ alkylethers thereof, benzyloxy, or halogen; or C₁-C₄ halogenated ethersincluding trifluoromethyl ether and trichloromethyl ether; R₂, R₃, R₅and R₆ are independently selected from H, OH or the C₁-C₁₂ esters orC₁-C₁₂ alkyl ethers thereof, halogens, or C₁-C₄ halogenated ethers,cyano, C₁-C₆ alkyl, or trifluoromethyl, with the proviso that, when R₁is H, R₂ is not OH; R₄ is selected from H, OH or the C₁-C₁₂ esters orC₁-C₁₂ alkyl ethers thereof, halogens, or C₁-C₄ halogenated ethers,benzyloxy, cyano, C₁-C₆ alkyl, or trifluoromethyl; X is selected from H,C₁-C₆ alkyl, cyano, nitro, trifluoromethyl, halogen; n is or 2 or 3; Yis selected from: a) the moiety:

wherein R₇ and R₈ are independently selected from the group of H, C₁-C₆alkyl, or phenyl optionally substituted by CN, C₁-C₆ alkyl, C₁-C₆alkoxy, halogen, —OH, —CF₃, or —OCF₃; b) a five-membered saturated,unsaturated or partially unsaturated heterocycle containing up to twoheteroatoms selected from the group consisting of —O—, —NH—, —N(C₁C₄alkyl)—, —N═, and —S(O)_(m)—, wherein m is an integer of from 0-2,optionally substituted with 1-3 substituents independently selected fromthe group consisting of hydrogen, hydroxyl, halo, C₁-C₄ alkyl,trihalomethyl, C₁-C₄ alkoxy, trihalomethoxy, C₁-C₄ acyloxy, C₁-C₄alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, hydroxy(C₁-C₄)alkyl, —CO₂H—, —CN—, —CONHR₁—, —NH₂—, C₁-C₄ alkylamino,di(C₁-C₄)alkylamino, —NHSO₂R₁—, —NHCOR₁—, —NO₂, and phenyl optionallysubstituted with 1-3 (C₁-C₄)alkyl; c) a six-membered saturated,unsaturated or partially unsaturated heterocycle containing up to twoheteroatoms selected from the group consisting of —O—, —NH—, —N(C₁C₄alkyl)—, —N═, and —S(O)_(m)—, wherein m is an integer of from 0-2,optionally substituted with 1-3 substituents independently selected fromthe group consisting of hydrogen, hydroxyl, halo, C₁-C₄ alkyl,trihalomethyl, C₁-C₄ alkoxy, trihalomethoxy, C₁-C₄ acyloxy, C₁-C₄alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, hydroxy(C₁-C₄)alkyl, —CO₂H—, —CN—, —CONHR₁—, —NH₂—, C₁-C₄ alkylamino,di(C₁-C₄)alkylamino, —NHSO₂R₁—, —NHCOR₁—, —NO₂, and phenyl optionallysubstituted with 1-3 (C₁-C₄)alkyl; d) a seven-membered saturated,unsaturated or partially unsaturated heterocycle containing up to twoheteroatoms selected from the group consisting of —O—, —NH—, —N(C₁C₄alkyl)—, —N═, and —S(O)_(m)—, wherein m is an integer of from 0-2,optionally substituted with 1-3 substituents independently selected fromthe group consisting of hydrogen, hydroxyl, halo, C₁-C₄ alkyl,trihalomethyl, C₁-C₄ alkoxy, trihalomethoxy, C₁-C₄ acyloxy, C₁-C₄alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, hydroxy(C₁-C₄)alkyl, —CO₂H—, —CN—, —CONHR₁—, —NH₂—, C₁-C₄ alkylamino,di(C₁-C₄)alkylamino, —NHSO₂R₁—, —NHCOR₁—, —NO₂, and phenyl optionallysubstituted with 1-3 (C₁-C₄)alkyl;; or e) a bicyclic heterocyclecontaining from 6-12 carbon atoms either bridged or fused and containingup to two heteroatoms selected from the group consisting of —O—, —NH—,—N(C₁C₄ alkyl)—, and —S(O)_(m)—, wherein m is an integer of from 0-2,optionally substituted with 1-3 substituents independently selected fromthe group consisting of hydrogen, hydroxyl, halo, C₁-C₄ alkyl,trihalomethyl, C₁-C₄ alkoxy, trihalomethoxy, C₁-C₄ acyloxy, C₁-C₄alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, hydroxy(C₁-C₄)alkyl, —CO₂H—, —CN—, —CONHR₁—, —NH₂—, C₁-C₄ alkylamino,di(C₁-C₄)alkylamino, —NHSO₂R₁—, —NHCOR₁—, —NO₂, and phenyl optionallysubstituted with 1-3 (C₁-C₄) alkyl; or a pharmaceutically acceptablesalt thereof.
 2. The method of claim 1 wherein in the compound of theformulae I or II: R₁ is selected from H, OH or the C₁-C₁₂ esters oralkyl ethers thereof, benzyloxy, or halogen; R₂, R₃, R₅, and R₆ areindependently selected from H, OH or the C₁-C₁₂ esters or alkyl ethersthereof, halogen, cyano, C₁-C₆ alkyl, or trihalomethyl; with the provisothat, when R₁ is H, R₂ is not OH; R₄ is selected from H, OH or theC₁-C₁₂ esters or alkyl ethers thereof, benzyloxy, halogen, cyano, C₁-C₆alkyl, or trihalomethyl; X is selected from H, C₁-C₆ alkyl, cyano,nitro, trifluoromethyl, halogen; Y is the moiety

R₇ and R₈ are selected independently from H, C₁-C₆ alkyl, or combined by—(CH₂)p—, wherein p is an integer of from 2 to 6, so as to form a ring,the ring being optionally substituted by up to three substituentsselected from the group of hydrogen, hydroxyl, halo, C₁-C₄ alkyl,trihalomethyl, C₁-C₄ alkoxy, trihalomethoxy, C₁-C₄ alkylthio, C₁-C₄alkylsulfinyl, C₁-C₄ alkylsulfonyl, hydroxy (C₁-C₄)alkyl, —CO₂H, —CN,—CONH(C₁-C₄), —NH₃, C₁-C₄ alkylamino, C₁-C₄ dialkylamino, —NHSO₂(C₁-C₄),—NHCO(C₁-C₄), and —NO₃; or a pharmaceutically acceptable salt thereof.3. The method of claim 2 wherein, in the compound of the formulae I orII, the ring formed by a the combination of R₇ and R₈ by —(CH₂)p— isselected from aziridine, azetidine, pyrrolidine, piperidine,hexamethyleneamine or heptamethyleneamine.
 4. The method of claim 1utilizing a compound of the formulae I or II, wherein R₁ is OH; R₂-R₆are as defined in claim 1; X is selected from the group of Cl, NO₂, CN,CF₃, or CH₃; and Y is the moiety

and R₇ and R₈ are concatenated together as —(CH₂)_(r)—, wherein r is aninteger of from 4 to 6, to form a ring optionally substituted by up tothree substituents selected from the group of hydrogen, hydroxyl, halo,C₁-C₄ alkyl, trihalomethyl, C₁-C₄ alkoxy, trihalomethoxy, C₁-C₄alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, hydroxy(C₁-C₄)alkyl, —CO₂H, —CN, —CONH(C₁-C₄)alkyl, —NH₂, C₁-C₄ alkylamino,di(C₁-C₄)alkylamino, —NHSO₂(C₁-C₄)alkyl, —NHCO(C₁-C₄)alkyl, and —NO₂; ora pharmaceutically acceptable salt thereof.
 5. The method of claim 1wherein the disease associated with an excess of neuropeptide Y isselected from epilepsy, cerebral infarction, epilepsy, neurodegenerativeconditions, stroke and related conditions, cerebral vasospasm orhemorrhage, anxiety, schizophrenia, depression or dementias.
 6. Themethod of claim 1 wherein the disease associated with an excess ofneuropeptide Y is selected from the group of anorexia nervosa, bulimia,metabolic disorders or obesity.
 7. The method of claim 1 wherein thedisease associated with an excess of neuropeptide Y is asthma.
 8. Amethod for treatment of diseases associated with an excess ofneuropeptide Y in a mammal, the method comprising administering to amammal in need thereof a pharmaceutically effective amount of a compoundof the formulae I or II:

wherein R₁, R₂, R₃, R₄, R₅, R₆, n, X, and Y are as defined in claim 1,or a pharmaceutically acceptable salt thereof.
 9. A method for treatmentof diseases associated with an excess of neuropeptide Y in a mammal, themethod comprising administering to a mammal in need thereof apharmaceutically effective amount of a compound of the formulae (V) or(VI):

wherein R₁, R₂, R₃, R₄, R₅, R₆, X, and Y are as defined in claim 1, or apharmaceutically acceptable salt thereof.
 10. A method for treatment ofdiseases associated with an excess of neuropeptide Y in a mammal, themethod comprising administering to a mammal in need thereof apharmaceutically effective amount of a compound of the formulae VII andVIII:

wherein R₁, R₂, R₃, R₄, R₅, R₆, n, X, and Y are as defined in claim 1,or a pharmaceutically acceptable salt thereof.
 11. A method fortreatment of breast disorders in a mammal, the method comprisingadministering to a mammal in need thereof a pharmaceutically effectiveamount of a compound of1-[4-(2-Azepan-1yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-indol-5-olor a pharmaceutically acceptable salt thereof.
 12. A method fortreatment of breast disorders in a mammal, the method comprisingadministering to a mammal in need thereof a pharmaceutically effectiveamount of a compound of2-(4-Hydroxy-phenyl)-3-methyl-1-(4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-olor a pharmaceutically acceptable salt thereof.